| Autor: |
Svenson, Ingrid K., Kloos, Mark T., Gaskell, P. Craig, Nance, Martha A., Garbern, James Y., Hisanaga, Shin-ichi, Pericak-Vance, Margaret A., Ashley-Koch, Allison E., Marchuk, Douglas A. |
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| Zdroj: |
Neurogenetics; Sep2004, Vol. 5 Issue 3, p157-164, 8p |
| Abstrakt: |
Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease characterized by wide variability in phenotypic expression, both within and among families. The most-common cause of autosomal dominant HSP is mutation of the gene encoding spastin, a protein of uncertain function. We report the existence of intragenic polymorphisms of spastin that modify the HSP phenotype. One (S44L) is a previously described recessively acting allele and the second is a novel allele affecting the adjacent amino acid residue (P45Q). In 4 HSP families in which either L44 or Q45 segregates independently of a missense or splicing mutation in the AAA domain of spastin, L44 and Q45 are each associated with a striking decrease in age at onset in the presence of the AAA domain mutations. Using a bio-informatics approach, we found that the highly conserved S44 is predicted to be phosphorylated by a number of family members of the proline-directed serine/threonine cyclin-dependent kinases (Cdks). Cdk1 and Cdk5 showed no kinase activity toward synthetic spastin peptide in an in vitro kinase assay, suggesting that this serine residue may be phosphorylated by a different Cdk. Our identification of S44L and P45Q as modifiers of the HSP phenotype suggests a role for spastin phosphorylation by Cdks in the neurodegeneration of the most-common form of HSP. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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